CA2389170C - A process for the production of epinastine hydrochloride in the high-melting crystal modification - Google Patents
A process for the production of epinastine hydrochloride in the high-melting crystal modification Download PDFInfo
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- CA2389170C CA2389170C CA002389170A CA2389170A CA2389170C CA 2389170 C CA2389170 C CA 2389170C CA 002389170 A CA002389170 A CA 002389170A CA 2389170 A CA2389170 A CA 2389170A CA 2389170 C CA2389170 C CA 2389170C
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- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960002548 epinastine hydrochloride Drugs 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims description 43
- 239000013078 crystal Substances 0.000 title abstract description 16
- 230000004048 modification Effects 0.000 title abstract description 15
- 238000012986 modification Methods 0.000 title abstract description 15
- 238000002844 melting Methods 0.000 title abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229960003449 epinastine Drugs 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical group CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 238000010533 azeotropic distillation Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims 2
- 239000000725 suspension Substances 0.000 claims 1
- 239000000047 product Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- DISXFZWKRTZTRI-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-2-amine Chemical class NC1=NCCN1 DISXFZWKRTZTRI-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003326 anti-histaminergic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- VKXSGUIOOQPGAF-UHFFFAOYSA-N epinastine hydrochloride Chemical compound [H+].[Cl-].C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 VKXSGUIOOQPGAF-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- -1 for example Chemical compound 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention relates to a process for preparing epinastine hydrochloride in the high-melting crystal modification.
Description
A process for the production of epinastine hydrochloride in the high-melting crystal modification The invention relates to a process for preparing epinastine hydrochloride in the high-melting crystal modification.
Background to the invention lo The compound epinastine (3-amino-9,13b-dihydro-1 H-dibenz-[c,f]imidazolo[1,5-a]-azepine) belongs to the 2-aminoimidazolines and is a therapeutically active substance characterised primarily by its antiallergenic and antihistaminergic activity (EP 35749).
Methods of preparing epinastine hydrochloride are known from the prior art. In EP
35749 epinastine hydrochloride is obtained by precipitation from a methanolic solution with ether. DE 41 02 148 discloses the formation of epinastine hydrochloride by reaction of the free epinastine base with HCI in dimethyl formamide. The abovementioned process for preparing epinastine hydrochloride which are known from the prior art do, however, have some disadvantages. Thus, epinastine hydrochloride cannot always be prepared in pure form using these methods or it is obtained in various crystal modifications. One known modification melts at about 250 to 263 C (low-melting crystal modification) and another melts at about 275-281 C (high-melting crystal modification). The use of alcohols in the precipitation of epinastine hydrochloride proposed in EP 35749 results in a loss of quality because of gradual decomposition of the product. In this process, the product also contains up to about 5% of the low-melting crystal modification, according to DSC (DSC = Differential Scannirig Calorimetry). The process for preparing epinastine hydrochloride disclosed by DE 41 02 148 involves the use of 3o dimethyl formamide, which can only be removed from the product of the process at high temperatures during drying, because of its high boiling point. As a result, the product begins to melt to some extent and changes colour. In addition, drying on an industrial scale requires an unacceptably high energy consumption.
Finally, dimethyl formamide is classed as being damaging to the foetus, which means that its presence in a pharmaceutical composition has to be avoided at all costs.
Case 1/1115 BOEHRINGER INGELHEIM PHARMA KG
Background to the invention lo The compound epinastine (3-amino-9,13b-dihydro-1 H-dibenz-[c,f]imidazolo[1,5-a]-azepine) belongs to the 2-aminoimidazolines and is a therapeutically active substance characterised primarily by its antiallergenic and antihistaminergic activity (EP 35749).
Methods of preparing epinastine hydrochloride are known from the prior art. In EP
35749 epinastine hydrochloride is obtained by precipitation from a methanolic solution with ether. DE 41 02 148 discloses the formation of epinastine hydrochloride by reaction of the free epinastine base with HCI in dimethyl formamide. The abovementioned process for preparing epinastine hydrochloride which are known from the prior art do, however, have some disadvantages. Thus, epinastine hydrochloride cannot always be prepared in pure form using these methods or it is obtained in various crystal modifications. One known modification melts at about 250 to 263 C (low-melting crystal modification) and another melts at about 275-281 C (high-melting crystal modification). The use of alcohols in the precipitation of epinastine hydrochloride proposed in EP 35749 results in a loss of quality because of gradual decomposition of the product. In this process, the product also contains up to about 5% of the low-melting crystal modification, according to DSC (DSC = Differential Scannirig Calorimetry). The process for preparing epinastine hydrochloride disclosed by DE 41 02 148 involves the use of 3o dimethyl formamide, which can only be removed from the product of the process at high temperatures during drying, because of its high boiling point. As a result, the product begins to melt to some extent and changes colour. In addition, drying on an industrial scale requires an unacceptably high energy consumption.
Finally, dimethyl formamide is classed as being damaging to the foetus, which means that its presence in a pharmaceutical composition has to be avoided at all costs.
Case 1/1115 BOEHRINGER INGELHEIM PHARMA KG
One aim of the present invention is to provide a process for preparing epinastine hydrochloride which avoids the disadvantages occurring in the processes known from the prior art.
Detailed description of the invention The invention relates to a process for preparing epinastine hydrochloride (formula I) (3-amino-9,13b-dihydro-1 H-dibenzo-[c,f]imidazolo[1,5-a]azepine-hydrochloride) in the high-melting crystal modification starting from epinastine base (I1) according to (Diagram 1).
Diagram 1:
HCI aq N solvent N x HCI
H2N~\N (II) H2N~\N (I) Another aim of the present invention is to provide a process for preparing epinastine hydrochloride which leads only to the formation of epinastine hydrochloride in the high-melting crystal modification. With regard to the pharmaceutical use of epinastine hydrochloride in conjunction with the statutory requirements for the quality control of pharmaceutical products it is absolutely 2o essential that pharmaceutical compositions containing epinastine hydrochloride should contain this active substance only in a single crystal modification.
The process according to the invention relates to the preparation of epinastine hydrochloride of formula (I) Px Nl (I) Case 1/1115 BOEHRINGER INGELHEIM PHARMA KG
Detailed description of the invention The invention relates to a process for preparing epinastine hydrochloride (formula I) (3-amino-9,13b-dihydro-1 H-dibenzo-[c,f]imidazolo[1,5-a]azepine-hydrochloride) in the high-melting crystal modification starting from epinastine base (I1) according to (Diagram 1).
Diagram 1:
HCI aq N solvent N x HCI
H2N~\N (II) H2N~\N (I) Another aim of the present invention is to provide a process for preparing epinastine hydrochloride which leads only to the formation of epinastine hydrochloride in the high-melting crystal modification. With regard to the pharmaceutical use of epinastine hydrochloride in conjunction with the statutory requirements for the quality control of pharmaceutical products it is absolutely 2o essential that pharmaceutical compositions containing epinastine hydrochloride should contain this active substance only in a single crystal modification.
The process according to the invention relates to the preparation of epinastine hydrochloride of formula (I) Px Nl (I) Case 1/1115 BOEHRINGER INGELHEIM PHARMA KG
characterised in that epinastine base of formula (II) N
H2N ~N
(II) is prepared by means of a process comprising - a first step in which epinastine base of formula (II) is suspended in water and dissolved by the addition of aqueous hydrochloric acid at a pH of >7, - a second step in which the aqueous solution obtainable from the first step is extracted with an organic, water-immiscible solvent and the extraction agent is subsequently removed and - a third step in which the product of formula (I) is precipitated from the aqueous solution obtained by means of the second step by the addition of hydrochloric acid at a pH of <6 and then dried.
According to the invention the following procedure is preferably used. In a suitably sized reaction vessel epinastine base (II) is suspended in water and dissolved at between 20 and 90 C, preferably 40 to 80 C, particularly preferably at 50 to 2o by the addition of aqueous hydrochloric acid at a pH which should not fall below 7.
At the same time, care should be taken to make the pH acidic enough for the epinastine base (II) to dissolve in water, but for the pH to remain basic enough to ensure that the epinastine hydrochloride (I) is not yet precipitated.
Preferably, the pH of the solution is between 7.5 and 9; a pH of 8 is particularly preferred.
The hydrochloric acid is preferably used in concentrated form, the term "concentrated form" meaning an approximately 32 % by weight aqueous hydrochloric acid.
The solution thus obtained is then extracted with the organic, water-immiscible solvent. Suitable solvents include, for example, halogenated hydrocarbons such 3o as methylene chloride, carbon tetrachloride, esters such as, for example, ethyl acetate or butyl acetate, ethers such as dimethyl or diethyl esters or other organic solvents known from the prior art for the extraction of aqueous phases.
Preferably, organic esters are used, especially butyl acetate.
Case 1/1115 BOEHRINGER INGELHEIM PHARMA KG
H2N ~N
(II) is prepared by means of a process comprising - a first step in which epinastine base of formula (II) is suspended in water and dissolved by the addition of aqueous hydrochloric acid at a pH of >7, - a second step in which the aqueous solution obtainable from the first step is extracted with an organic, water-immiscible solvent and the extraction agent is subsequently removed and - a third step in which the product of formula (I) is precipitated from the aqueous solution obtained by means of the second step by the addition of hydrochloric acid at a pH of <6 and then dried.
According to the invention the following procedure is preferably used. In a suitably sized reaction vessel epinastine base (II) is suspended in water and dissolved at between 20 and 90 C, preferably 40 to 80 C, particularly preferably at 50 to 2o by the addition of aqueous hydrochloric acid at a pH which should not fall below 7.
At the same time, care should be taken to make the pH acidic enough for the epinastine base (II) to dissolve in water, but for the pH to remain basic enough to ensure that the epinastine hydrochloride (I) is not yet precipitated.
Preferably, the pH of the solution is between 7.5 and 9; a pH of 8 is particularly preferred.
The hydrochloric acid is preferably used in concentrated form, the term "concentrated form" meaning an approximately 32 % by weight aqueous hydrochloric acid.
The solution thus obtained is then extracted with the organic, water-immiscible solvent. Suitable solvents include, for example, halogenated hydrocarbons such 3o as methylene chloride, carbon tetrachloride, esters such as, for example, ethyl acetate or butyl acetate, ethers such as dimethyl or diethyl esters or other organic solvents known from the prior art for the extraction of aqueous phases.
Preferably, organic esters are used, especially butyl acetate.
Case 1/1115 BOEHRINGER INGELHEIM PHARMA KG
The solution is extracted at least once, preferably several times, with the organic solvent. After the organic solvent has been separated off, any residual amounts of the organic solvent in the aqueous phase are removed by azeotropic distillation.
Therefore the organic solvents used for the extraction are preferably those which can be removed from water by azeotropic distillation.
Activated charcoal is added to the resulting aqueous solution in the warm and is filtered off again after some time. Preferably, the mixture is stirred for some time at a temperature of between >50 C and 100 C, preferably between 70 C and io 95 C, most preferably at 80 C to 90 C.
After filtration, the clear solution is cooled to below 50 C and the pH is adjusted to <6 with hydrochloric acid, preferably concentrated hydrochloric acid. The pH
is preferably adjusted to 3 to 5, most preferably 3.5 to 4.5. The temperature of the solution should not fall below 25 C, so as to prevent premature crystallisation of the product. The temperature is preferably maintained between 30 C and 40 C.
As soon as the desired pH has been achieved, the solution is carefully cooled with stirring, preferably to about 20 C. After a few minutes the product (1) is spontaneously precipitated, with the development of heat, which should be 2o removed by cooling:
After crystallisation is complete, which may if desired by accelerated and/or completed by cooling, the crystal slurry is filtered off and washed with water. Ice water is preferably used for the washing. The product is then dried.
Any unprecipitated product still present in the filtrate can be precipitated using methods known from the prior art.
The product obtained by this process is pure epinastine hydrochloride (I) in the 3o higher-melting crystal modification, according to the usual methods of analysis.
With the process according to the invention it is possible to obtain yields of the product (I) in the higher-melting crystal modification of over 80% of theory.
If the purity of the product does not meet the particular requirements, the process can be repeated. If necessary, the last stages are repeated.
Case 1/1115 BOEHRINGER INGELHEIM PHARMA KG
The advantage of the process according to the invention is that, compared with the process known from the prior art, dimethyl formamide is totally replaced by water. This advantageously improves the pharmaceutical quality of the product (I), since among other things the product does not contain any residual traces of 5 dimethyl formamide or its breakdown products and the product can be dried at moderate temperatures.
Exam ie 1o Epinastine base (124.5 g) is suspended in a defined amount of water (390 ml) and the pH is adjusted to 8 at a temperature of 60 C by the addition of 32%
hydrochloric acid (about 50 ml). After the aqueous solution has twice been extracted with butyl acetate at 60 C (150 ml and 75 ml) and the organic phase has been separated off, some of the water is distilled off under normal pressure in order to eliminate the residual butyl acetate azeotropically. Then activated charcoal (LX - Ultra, moistened with water) is added to the residue at about 90 C, this is stirred for 30 minutes and the product solution is then filtered till clear and the charcoal filtered off is washed with about 12.5 ml of water. Hydroch(oric acid is metered into the clear filtered solution at 30 - 40 C until a pH of 3.5 - 4.5 is obtained (about 1 ml), it is then cooled to 20 C and inoculated with epinastine hydrochloride (containing water of crystallisation and moistened with water).
After about 5 - 10 min. a thick crystal slurry has formed, while the temperature has risen slightly.
To complete the crystallisation the mixture is stirred for about another 30-45 min.
at 20 C, then cooled to 0-5 C in 1-2 hours, stirred for another 30 min. at 0-5 C, the crystals are suction filtered and washed'with ice-cold water (about 100 ml).
The yield is 86.8% of theory. This can be increased to 90 % of theory by 3o recovering an after-yield.
According to the DSC plot in Figure 1 the product obtained is the desired high-melting modification of epinastine hydrochloride.
Therefore the organic solvents used for the extraction are preferably those which can be removed from water by azeotropic distillation.
Activated charcoal is added to the resulting aqueous solution in the warm and is filtered off again after some time. Preferably, the mixture is stirred for some time at a temperature of between >50 C and 100 C, preferably between 70 C and io 95 C, most preferably at 80 C to 90 C.
After filtration, the clear solution is cooled to below 50 C and the pH is adjusted to <6 with hydrochloric acid, preferably concentrated hydrochloric acid. The pH
is preferably adjusted to 3 to 5, most preferably 3.5 to 4.5. The temperature of the solution should not fall below 25 C, so as to prevent premature crystallisation of the product. The temperature is preferably maintained between 30 C and 40 C.
As soon as the desired pH has been achieved, the solution is carefully cooled with stirring, preferably to about 20 C. After a few minutes the product (1) is spontaneously precipitated, with the development of heat, which should be 2o removed by cooling:
After crystallisation is complete, which may if desired by accelerated and/or completed by cooling, the crystal slurry is filtered off and washed with water. Ice water is preferably used for the washing. The product is then dried.
Any unprecipitated product still present in the filtrate can be precipitated using methods known from the prior art.
The product obtained by this process is pure epinastine hydrochloride (I) in the 3o higher-melting crystal modification, according to the usual methods of analysis.
With the process according to the invention it is possible to obtain yields of the product (I) in the higher-melting crystal modification of over 80% of theory.
If the purity of the product does not meet the particular requirements, the process can be repeated. If necessary, the last stages are repeated.
Case 1/1115 BOEHRINGER INGELHEIM PHARMA KG
The advantage of the process according to the invention is that, compared with the process known from the prior art, dimethyl formamide is totally replaced by water. This advantageously improves the pharmaceutical quality of the product (I), since among other things the product does not contain any residual traces of 5 dimethyl formamide or its breakdown products and the product can be dried at moderate temperatures.
Exam ie 1o Epinastine base (124.5 g) is suspended in a defined amount of water (390 ml) and the pH is adjusted to 8 at a temperature of 60 C by the addition of 32%
hydrochloric acid (about 50 ml). After the aqueous solution has twice been extracted with butyl acetate at 60 C (150 ml and 75 ml) and the organic phase has been separated off, some of the water is distilled off under normal pressure in order to eliminate the residual butyl acetate azeotropically. Then activated charcoal (LX - Ultra, moistened with water) is added to the residue at about 90 C, this is stirred for 30 minutes and the product solution is then filtered till clear and the charcoal filtered off is washed with about 12.5 ml of water. Hydroch(oric acid is metered into the clear filtered solution at 30 - 40 C until a pH of 3.5 - 4.5 is obtained (about 1 ml), it is then cooled to 20 C and inoculated with epinastine hydrochloride (containing water of crystallisation and moistened with water).
After about 5 - 10 min. a thick crystal slurry has formed, while the temperature has risen slightly.
To complete the crystallisation the mixture is stirred for about another 30-45 min.
at 20 C, then cooled to 0-5 C in 1-2 hours, stirred for another 30 min. at 0-5 C, the crystals are suction filtered and washed'with ice-cold water (about 100 ml).
The yield is 86.8% of theory. This can be increased to 90 % of theory by 3o recovering an after-yield.
According to the DSC plot in Figure 1 the product obtained is the desired high-melting modification of epinastine hydrochloride.
Claims (17)
CLAIMS:
1. A process for preparing epinastine hydrochloride of formula (I) wherein an epinastine base of formula (II) is prepared by means of a process comprising - a first step in which epinastine base of formula (II) is suspended in water and dissolved by the addition of aqueous hydrochloric acid at a pH of >=7, - a second step in which the aqueous solution obtained from the first step is extracted with an organic, water-immiscible solvent and the extraction agent is subsequently removed and - a third step in which the product of formula (I) is precipitated from the aqueous solution obtained by means of the second step by the addition of hydrochloric acid at a pH of <= 6 and then dried.
2. A process according to claim 1, wherein the suspension of the epinastine base of formula (II) is combined with the hydrochloric acid in the first step of the process at a temperature of between 20 and 90°C.
3. A process according to claim 2, wherein the temperature is 40 to 80°C.
4. A process according to claim 2, wherein the temperature is 50 to 70°C.
5. A process according to any one of claims 1 to 4, wherein the pH during the first step of the process is between 7.5 and 9.
6. A process according to any one of claims 1 to 4, wherein the pH during the first step of the process is 8.
7. A process according to any one of claims 1 to 6, wherein a halogenated hydrocarbon, an ether or an ester is used in the second step of the process.
8. A process according to claim 7, wherein the halogenated hydrocarbon, ether or ester is ethyl acetate.
9. A process according to claim 7, wherein the halogenated hydrocarbon, ether or ester is butyl acetate.
10. A process according to any one of claims 1 to 9, wherein the extraction agent in the second step of the process is eliminated by one or both of decanting and azeotropic distillation.
11. A process according to any one of claims 1 to 10, wherein between the second and third steps of the process the aqueous phase is purified using activated charcoal at a temperature of between 50°C and 100°C.
12. A process according to claim 11, wherein the purification temperature is 70°C to 95°C.
13. A process according to claim 11, wherein the purification temperature is 80°C to 90°C.
14. A process according to any one of claims 1 to 13, wherein in the third step of the process the pH is adjusted to 3 to 5 by the addition of the hydrochloric acid.
15. A process according to any one of claims 1 to 13, wherein in the third step of the process the pH is adjusted to 3.5 to 4.5 by the addition of the hydrochloric acid.
16. A process according to any one of claims 1 to 15, wherein in the third step of the process the hydrochloric acid is added at a temperature of 25°C to 50°C and then the aqueous phase is left to cool.
17. A process according to any one of claims 1 to 15, wherein in the third step of the process the hydrochloric acid is added at a temperature of 30°C to 50°C and then the aqueous phase is left to cool.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19958460.5 | 1999-12-03 | ||
| DE19958460A DE19958460A1 (en) | 1999-12-03 | 1999-12-03 | Process for the preparation of epinastine hydrochloride in high-melting crystal modification |
| PCT/EP2000/011942 WO2001040229A2 (en) | 1999-12-03 | 2000-11-29 | Method for producing epinastine hydrochloride in the high-melting crystal modification |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2389170A1 CA2389170A1 (en) | 2001-06-07 |
| CA2389170C true CA2389170C (en) | 2008-01-08 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002389170A Expired - Lifetime CA2389170C (en) | 1999-12-03 | 2000-11-29 | A process for the production of epinastine hydrochloride in the high-melting crystal modification |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US6403790B1 (en) |
| EP (1) | EP1237892B1 (en) |
| JP (1) | JP4789383B2 (en) |
| KR (1) | KR100737191B1 (en) |
| CN (1) | CN1402728A (en) |
| AR (1) | AR026678A1 (en) |
| AT (1) | ATE238306T1 (en) |
| AU (1) | AU2163501A (en) |
| BR (1) | BR0016052A (en) |
| CA (1) | CA2389170C (en) |
| CO (1) | CO5251470A1 (en) |
| CZ (1) | CZ20021843A3 (en) |
| DE (2) | DE19958460A1 (en) |
| DK (1) | DK1237892T3 (en) |
| EA (1) | EA200200630A1 (en) |
| ES (1) | ES2198368T3 (en) |
| HU (1) | HUP0203501A2 (en) |
| IL (1) | IL149711A0 (en) |
| MX (1) | MXPA02005330A (en) |
| PL (1) | PL355628A1 (en) |
| PT (1) | PT1237892E (en) |
| UY (1) | UY26461A1 (en) |
| WO (1) | WO2001040229A2 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19954516A1 (en) * | 1999-11-12 | 2001-05-17 | Boehringer Ingelheim Int | Solutions containing epinastine |
| JP4298212B2 (en) * | 2002-03-29 | 2009-07-15 | 大日本印刷株式会社 | Method for producing high melting point type epinastine hydrochloride |
| WO2004014353A1 (en) * | 2002-08-02 | 2004-02-19 | Boehringer Ingelheim International Gmbh | Pharmaceutical formulations comprising combinations of epinastine, pseudoephedrine and methylephedrine |
| KR101386530B1 (en) | 2006-12-29 | 2014-04-18 | 케이피엑스 라이프사이언스 주식회사 | Preparation method for 3-amino-9,13b-dihydro-1H-dibenz-[c,f]imidazo[1,5-a]-azepine hydrochloride having improved purity and yield |
| CN104098575B (en) * | 2013-04-15 | 2016-06-01 | 四川科瑞德凯华制药有限公司 | Brilliant type of a kind of Epinastine Hydrochloride and its production and use |
| CN115448927A (en) * | 2022-10-20 | 2022-12-09 | 重庆瑞泊莱医药科技有限公司 | Epinastine hydrobromide crystal form II and preparation method thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3008944A1 (en) * | 1980-03-08 | 1981-09-24 | C.H. Boehringer Sohn, 6507 Ingelheim | DIBENZIMIDAZOAZEPINE, THEIR PRODUCTION AND USE |
| DE4102148A1 (en) * | 1991-01-25 | 1992-07-30 | Boehringer Ingelheim Kg | METHOD FOR PRODUCING 3-AMINO-9,13B-DIHYDRO-1H-DIBENZ- (C, F) IMIDAZOLE (1,5-A) AZEPINE HYDROCHLORIDE |
| JP3726291B2 (en) * | 1993-07-05 | 2005-12-14 | 三菱ウェルファーマ株式会社 | Benzoxazine compound having stable crystal structure and process for producing the same |
| JPH083160A (en) * | 1994-06-22 | 1996-01-09 | Nippon Kayaku Co Ltd | Method for separating and purifying 6-(1-h-imidazol-1-yl)-7-nitro-2,3-(1h,4h)-quinoxalinedione hydrochloride or sulfate |
| JP3755908B2 (en) * | 1994-08-17 | 2006-03-15 | 塩野義製薬株式会社 | Crystallization of cephalosporin compounds |
| JPH0948765A (en) * | 1995-08-04 | 1997-02-18 | Toyama Chem Co Ltd | Triazole derivative having stable crystal structure and method for producing the same |
| DE19542281C2 (en) * | 1995-11-14 | 1997-12-04 | Boehringer Ingelheim Kg | Use of Epinastin for the treatment of migraines |
-
1999
- 1999-12-03 DE DE19958460A patent/DE19958460A1/en not_active Withdrawn
-
2000
- 2000-11-20 US US09/716,355 patent/US6403790B1/en not_active Expired - Lifetime
- 2000-11-29 JP JP2001540984A patent/JP4789383B2/en not_active Expired - Lifetime
- 2000-11-29 EA EA200200630A patent/EA200200630A1/en unknown
- 2000-11-29 ES ES00985110T patent/ES2198368T3/en not_active Expired - Lifetime
- 2000-11-29 CN CN00816517A patent/CN1402728A/en active Pending
- 2000-11-29 AU AU21635/01A patent/AU2163501A/en not_active Abandoned
- 2000-11-29 BR BR0016052-0A patent/BR0016052A/en not_active Application Discontinuation
- 2000-11-29 IL IL14971100A patent/IL149711A0/en unknown
- 2000-11-29 CZ CZ20021843A patent/CZ20021843A3/en unknown
- 2000-11-29 UY UY26461A patent/UY26461A1/en not_active Application Discontinuation
- 2000-11-29 DK DK00985110T patent/DK1237892T3/en active
- 2000-11-29 MX MXPA02005330A patent/MXPA02005330A/en active IP Right Grant
- 2000-11-29 AT AT00985110T patent/ATE238306T1/en active
- 2000-11-29 PT PT00985110T patent/PT1237892E/en unknown
- 2000-11-29 PL PL00355628A patent/PL355628A1/en not_active Application Discontinuation
- 2000-11-29 EP EP00985110A patent/EP1237892B1/en not_active Expired - Lifetime
- 2000-11-29 CA CA002389170A patent/CA2389170C/en not_active Expired - Lifetime
- 2000-11-29 WO PCT/EP2000/011942 patent/WO2001040229A2/en not_active Ceased
- 2000-11-29 KR KR1020027007120A patent/KR100737191B1/en not_active Expired - Lifetime
- 2000-11-29 HU HU0203501A patent/HUP0203501A2/en unknown
- 2000-11-29 DE DE50001920T patent/DE50001920D1/en not_active Expired - Lifetime
- 2000-12-01 CO CO00092015A patent/CO5251470A1/en not_active Application Discontinuation
- 2000-12-01 AR ARP000106338A patent/AR026678A1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| PL355628A1 (en) | 2004-05-04 |
| WO2001040229A3 (en) | 2001-12-06 |
| AR026678A1 (en) | 2003-02-19 |
| DE50001920D1 (en) | 2003-05-28 |
| UY26461A1 (en) | 2001-07-31 |
| ES2198368T3 (en) | 2004-02-01 |
| IL149711A0 (en) | 2002-11-10 |
| ATE238306T1 (en) | 2003-05-15 |
| DE19958460A1 (en) | 2001-06-07 |
| EP1237892A2 (en) | 2002-09-11 |
| EP1237892B1 (en) | 2003-04-23 |
| PT1237892E (en) | 2003-08-29 |
| MXPA02005330A (en) | 2003-01-28 |
| US6403790B1 (en) | 2002-06-11 |
| EA200200630A1 (en) | 2002-12-26 |
| KR20020058080A (en) | 2002-07-12 |
| HUP0203501A2 (en) | 2003-03-28 |
| JP2003515536A (en) | 2003-05-07 |
| KR100737191B1 (en) | 2007-07-10 |
| CZ20021843A3 (en) | 2002-08-14 |
| WO2001040229A2 (en) | 2001-06-07 |
| CO5251470A1 (en) | 2003-02-28 |
| CA2389170A1 (en) | 2001-06-07 |
| BR0016052A (en) | 2002-07-23 |
| DK1237892T3 (en) | 2003-08-04 |
| AU2163501A (en) | 2001-06-12 |
| JP4789383B2 (en) | 2011-10-12 |
| CN1402728A (en) | 2003-03-12 |
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